A nonimmunoglobulin protein (A protein) has been isolated from amyloidotic tissue of secondary type. Antisera prepared to this protein identified a cross-reacting substance in the sera of patients with secondary amyloidosis. Sera from 70 persons with amyloidosis, 120 normal adults, 20 aged persons, and 97 patients with chronic diseases were tested for this substance. One hundred percent of secondary amyloid sera had amounts of amyloid serum component detectable by double diffusion in agar, whereas only 19 percent of primary amyloid sera were positive. Approximately 60 percent of rheumatoid sera as well as 60 per cent of sera from aged individuals were positive. Only 3 percent or normal blood donors had detectable amounts of this circulating substance. Isolation of the serum component by affinity chromatography and partial characterization have shown that it is an alpha-globulins with a molecular weight of 100,000-120,000, that it is not related antigenically to immunoglobulin or amyloid P-compoment, and that it has an amino acid analysis that is markedly different from tissue A protein. The possible participation of this substance in the genesis of amyloid is discussed.